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Reduction of soluble CD163, substance P, programmed death 1 and inflammatory markers: phase 1B trial of aprepitant in HIV-1-infected adults

OBJECTIVE: We evaluated safety, antiviral, immunomodulatory and anti-inflammatory properties of aprepitant – a neurokinin 1 receptor antagonist. DESIGN: Phase IB randomized, placebo-controlled, double-blinded study. METHODS: Eighteen patients were randomized (nine to aprepitant and nine to placebo)....

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Autores principales: Tebas, Pablo, Spitsin, Sergei, Barrett, Jeffrey S., Tuluc, Florin, Elci, Okan, Korelitz, James J., Wagner, Wayne, Winters, Angela, Kim, Deborah, Catalano, Renae, Evans, Dwight L., Douglas, Steven D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Lippincott Williams & Wilkins 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4472318/
https://www.ncbi.nlm.nih.gov/pubmed/25915168
http://dx.doi.org/10.1097/QAD.0000000000000638
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author Tebas, Pablo
Spitsin, Sergei
Barrett, Jeffrey S.
Tuluc, Florin
Elci, Okan
Korelitz, James J.
Wagner, Wayne
Winters, Angela
Kim, Deborah
Catalano, Renae
Evans, Dwight L.
Douglas, Steven D.
author_facet Tebas, Pablo
Spitsin, Sergei
Barrett, Jeffrey S.
Tuluc, Florin
Elci, Okan
Korelitz, James J.
Wagner, Wayne
Winters, Angela
Kim, Deborah
Catalano, Renae
Evans, Dwight L.
Douglas, Steven D.
author_sort Tebas, Pablo
collection PubMed
description OBJECTIVE: We evaluated safety, antiviral, immunomodulatory and anti-inflammatory properties of aprepitant – a neurokinin 1 receptor antagonist. DESIGN: Phase IB randomized, placebo-controlled, double-blinded study. METHODS: Eighteen patients were randomized (nine to aprepitant and nine to placebo). The patients received once-daily treatment (375 mg aprepitant or placebo by oral administration) for 2 weeks and were followed off drug for 4 weeks. RESULTS: There were no significant changes in the plasma viremia or CD4(+) T cells during the dosing period. Aprepitant treatment was associated with significant decreases of median within patient change in percentages of CD4(+) T cells expressing programmed death 1 (−4.8%; P = 0.04), plasma substance P (−34.0 pg/ml; P = 0.05) and soluble CD163 (−563 ng/ml; P = 0.02), with no significant changes in the placebo arm. Mean peak aprepitant plasma concentration on day 14 was 7.6 ± 3.1 μg/ml. The use of aprepitant was associated with moderate increases in total cholesterol, low-density lipoprotein and high-density lipoprotein (median change = +31 mg/dl, P = 0.01; +26 mg/dl, P = 0.02; +3 mg/dl, P = 0.02, respectively). CONCLUSION: Aprepitant was safe and well tolerated. At the dose used in this proof-of-concept phase IB study, aprepitant did not show a significant antiviral activity. Aprepitant-treated patients had decreased numbers of CD4(+) programmed death 1-positive cells and decreased plasma levels of substance P and soluble CD163, suggesting that blockade of the neurokinin 1 receptor pathway has a role in modulating monocyte activation in HIV infection. Prospective studies in virologically-suppressed individuals are warranted to evaluate the immunomodulatory properties of aprepitant. Exposures exceeding those attained in this trial are more likely to elicit clinical benefit.
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spelling pubmed-44723182015-06-30 Reduction of soluble CD163, substance P, programmed death 1 and inflammatory markers: phase 1B trial of aprepitant in HIV-1-infected adults Tebas, Pablo Spitsin, Sergei Barrett, Jeffrey S. Tuluc, Florin Elci, Okan Korelitz, James J. Wagner, Wayne Winters, Angela Kim, Deborah Catalano, Renae Evans, Dwight L. Douglas, Steven D. AIDS Clinical Science OBJECTIVE: We evaluated safety, antiviral, immunomodulatory and anti-inflammatory properties of aprepitant – a neurokinin 1 receptor antagonist. DESIGN: Phase IB randomized, placebo-controlled, double-blinded study. METHODS: Eighteen patients were randomized (nine to aprepitant and nine to placebo). The patients received once-daily treatment (375 mg aprepitant or placebo by oral administration) for 2 weeks and were followed off drug for 4 weeks. RESULTS: There were no significant changes in the plasma viremia or CD4(+) T cells during the dosing period. Aprepitant treatment was associated with significant decreases of median within patient change in percentages of CD4(+) T cells expressing programmed death 1 (−4.8%; P = 0.04), plasma substance P (−34.0 pg/ml; P = 0.05) and soluble CD163 (−563 ng/ml; P = 0.02), with no significant changes in the placebo arm. Mean peak aprepitant plasma concentration on day 14 was 7.6 ± 3.1 μg/ml. The use of aprepitant was associated with moderate increases in total cholesterol, low-density lipoprotein and high-density lipoprotein (median change = +31 mg/dl, P = 0.01; +26 mg/dl, P = 0.02; +3 mg/dl, P = 0.02, respectively). CONCLUSION: Aprepitant was safe and well tolerated. At the dose used in this proof-of-concept phase IB study, aprepitant did not show a significant antiviral activity. Aprepitant-treated patients had decreased numbers of CD4(+) programmed death 1-positive cells and decreased plasma levels of substance P and soluble CD163, suggesting that blockade of the neurokinin 1 receptor pathway has a role in modulating monocyte activation in HIV infection. Prospective studies in virologically-suppressed individuals are warranted to evaluate the immunomodulatory properties of aprepitant. Exposures exceeding those attained in this trial are more likely to elicit clinical benefit. Lippincott Williams & Wilkins 2015-05-15 2015-05-06 /pmc/articles/PMC4472318/ /pubmed/25915168 http://dx.doi.org/10.1097/QAD.0000000000000638 Text en Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. http://creativecommons.org/licenses/by-nc-nd/4.0 This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/4.0
spellingShingle Clinical Science
Tebas, Pablo
Spitsin, Sergei
Barrett, Jeffrey S.
Tuluc, Florin
Elci, Okan
Korelitz, James J.
Wagner, Wayne
Winters, Angela
Kim, Deborah
Catalano, Renae
Evans, Dwight L.
Douglas, Steven D.
Reduction of soluble CD163, substance P, programmed death 1 and inflammatory markers: phase 1B trial of aprepitant in HIV-1-infected adults
title Reduction of soluble CD163, substance P, programmed death 1 and inflammatory markers: phase 1B trial of aprepitant in HIV-1-infected adults
title_full Reduction of soluble CD163, substance P, programmed death 1 and inflammatory markers: phase 1B trial of aprepitant in HIV-1-infected adults
title_fullStr Reduction of soluble CD163, substance P, programmed death 1 and inflammatory markers: phase 1B trial of aprepitant in HIV-1-infected adults
title_full_unstemmed Reduction of soluble CD163, substance P, programmed death 1 and inflammatory markers: phase 1B trial of aprepitant in HIV-1-infected adults
title_short Reduction of soluble CD163, substance P, programmed death 1 and inflammatory markers: phase 1B trial of aprepitant in HIV-1-infected adults
title_sort reduction of soluble cd163, substance p, programmed death 1 and inflammatory markers: phase 1b trial of aprepitant in hiv-1-infected adults
topic Clinical Science
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4472318/
https://www.ncbi.nlm.nih.gov/pubmed/25915168
http://dx.doi.org/10.1097/QAD.0000000000000638
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